Alpha synuclein deficiency increases CD4 + T-cells pro-inflammatory profile in a Nurr1-dependent manner.

It has been suggested that extracellular alpha synuclein (alpha Syn) can mediate neuroinflammation in Parkinson's disease, and that alpha Syn affects B-cell maturation. However, the function of alpha Syn in T cells is poorly understood. We hypothesized that alpha Syn can affect CD4(+) T-cell proliferation and activity. We found that alpha Syn deficiency exacerbates disease progression in 8 weeks old C57BL6/J EAE-induced mice, and that alpha Syn-deficient CD4(+) T cells have increased pro-inflammatory response to myelin antigen relative to wild-type cells, as measured by cytokine secretion of interleukin IL-17 and interferon gamma. Furthermore, expression of alpha Syn on a background of alpha Syn knockout mitigates the inflammatory responses in CD4(+) T cells. We discovered that elevated levels of Nurr1, a transcription factor belonging to the orphan nuclear receptor family, are associated with the pro-inflammatory profile of alpha Syn-deficient CD4(+) T cells. In addition, we demonstrated that silencing of Nurr1 expression using an siRNA reduces IL-17 levels and increases the levels of IL-10, an anti-inflammatory cytokine. Study of alpha Syn-mediated cellular pathways in CD4(+) T cells may provide useful insights into the development of pro-inflammatory responses in immunity, providing future avenues for therapeutic intervention.